This invention relates to processes for the production of aminoalkyl glucosaminide phosphate (AGP) and of disaccharide compounds. Such compounds have been found to be immunoeffectors, adjuvants for vaccines and the like, and in addition, can possess therapeutic and/or prophylactic properties of their own. In addition, this invention relates to processes for the production of glycosyl halides, which can serve as intermediates in the synthesis of AGP compounds, disaccharides, and structurally related molecules. Further, this invention relates to an improved method for synthesizing (R)-3-n-alkanoyltetradecanoic acids, which are intermdiates utilized in production of AGPs.
Aminoalkyl glucosaminide phosphates are described in a number of patents, published patent applications, and journal articles. Such compounds in general have five or six acyl groups in the molecular structure, together with an “aglycon” (nitrogen-containing portion), which may be cyclical or acyclical. AGPs having acyclical aglycon groups are disclosed, for instance, in U.S. Pat. Nos. 6,113,918; 6,303,347 and 6,355,257. AGPs having cyclical aglycon groups are disclosed, for instance, in WO 02/012258.
The above-mentioned documents describe the production of the AGP compounds by two alternative processes. In one process a protected 3-O-acyloxyacylated glycosyl halide containing a phosphonate side chain is coupled with an aminoalkanol or aminoalkanethiol of the type described in the patents. The reaction product is then selectively acylated to provide additional acyl groups, as described, and protecting groups are removed. In the second process, both the phosphonate side chain and the fatty acid groups are incorporated after the coupling reaction. Additional process information for producing AGP compounds is contained in Johnson et al., Bioorg. Med. Chem. Lett. 9: 2273 (1999).
Disaccharides that may be produced by the processes described herein include components of the well known immunostimulant monophosphoryl lipid A (contained, for example in MPL® immunostimulant (Corixa Corp.) Other disaccharides that may be produced are disclosed in, for instance, PCT application WO 01/90129 and U.S. Pat. Nos. 6,013,640; 4,987,237; 4,912,094; 4,436,727; and 4,436,728. In U.S. Pat. No. 6,103,640 the disaccharide was prepared by coupling an N-acyloxyacylated or N-protected glycosyl acceptor unit with a protected and/or 3-O-acyloxyacylated glycosyl donor unit. The protecting groups were variously benzyl (Bn) and 2,2,2-trichloroethoxycarbonyl (Troc) groups. The glycosyl acceptor and donor units were constructed separately using a series of substituent protection and deprotection steps, beginning with the known starting materials benzyl- and 2-(trimethylsilyl)ethyl-2-amino-2-deoxy-4,6-O-isopropylidene-β-D-glucopyranoside, respectively.
Glycosyl halides are used in many processes to introduce a glycoside moiety into a molecule, typically as part of a multistep synthesis in the field of saccharide chemistry. They are useful intermediates for incorporating a wide variety of groups, typically by reaction with nucleophiles, especially oxygen, sulfur, and nitrogen nucleophiles. It would be advantageous to provide a process for producing the AGP and disaccharide compounds using a glycosyl halide as a starting material.
Various ways of producing glycosyl halides have been described. Generally, they involve halogenation of an existing glycoside (which may contain typical protecting groups on reactive moieties such as amino or hydroxyl).
In U.S. Pat. No. 6,299,897, for example, an ethyl ester of the glycoside in question (in this instance, N-acetyl neuraminic acid) is reacted with acetyl chloride to produce the corresponding glycosyl chloride. In U.S. Pat. No. 5,843,463, a glycosyl chloride is produced by reacting the glycoside in question (3-O-allyl-5-O-benzyl-1,2-O-methoxybenzylidene-alpha-D-ribofuranose) with trimethylsilyl chloride. The reaction is conducted by mixing the two reactants or by dissolving the glycoside in the trimethylsilyl chloride.
U.S. Pat. No. 4,613,590 discloses a process for preparation of glycosyl chloride by treatment of the glycoside with titanium tetrachloride. In Sugiyama et al., Org. Lett. 2: 2713 (2000), glycosyl chlorides were prepared by reaction of thioglycosides with chlorosulfoniun chloride.
Kovac, Carbohydr. Res. 245: 219 (1993) prepared a glycosyl chloride by reaction of the glycoside with dichloromethyl methyl ether and zinc chloride. Takeo et al., Carbohydr. Res. 245: 81 (1993) produced a glycosyl chloride by reaction with chlorine. Magnusson et al., J. Org. Chem. 55:3181 (1990) produced a glycosyl chloride by reaction of the 2-(trimethylsilyl)ethyl glycoside with 1,1-dichloromethyl methyl ether in the presence of a catalytic amount of zinc chloride.